Helicobacter pylori specifically colonizes the human gastric epithelium and is the major causative agent for ulcer disease and gastric cancer development. Here we identified members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family as novel receptors of H. pylori and show that HopQ is the surface-exposed adhesin that specifically binds human CEACAM1, CEACAM3, CEACAM5 and CEACAM6. HopQ-CEACAM binding is glycan-independent and targeted to the N-domain. H. pylori binding induces CEACAM1 mediated signaling, and the HopQ-CEACAM1 interaction enables translocation of the virulence factor CagA into host cells, and enhances the release of proinflammatory mediators such as interleukin-8. Based on the crystal structure of HopQ, we found that a β-hairpin insertion (HopQ-ID) in HopQ's extracellular 3+4 helix bundle domain is important for CEACAM binding. A peptide derived from this domain competitively inhibits HopQ-mediated activation of the Cag virulence pathway, as genetic or antibodymediated abrogation of the HopQ function shows. Together, our data imply the HopQ-CEACAM1 interaction as potentially promising novel therapeutic target to combat H. pyloriassociated diseases. Helicobacter pylori (H. pylori) is one of the most prevalent human pathogens, colonizing half of the world's population. Chronic inflammation elicited by this bacterium is the main cause of gastric cancer 1. During co-evolution with it's human host over more than 60.000 years 2 , the bacterium has acquired numerous adaptations for the long-term survival within its unique niche, the stomach. This includes the ability to buffer the extreme acidity of this environment, the interference with cellular signaling pathways, the evasion of the human immune response and a strong adhesive property to host cells 3. Specifically, H. pylori persistence is facilitated by the binding of BabA and SabA adhesins to the human blood group antigen Leb and the sLex antigen, respectively 4-6. However, adhesion to blood group antigens is not universal, is dynamically regulated during the course of infection and can also be turned off 7. We observed that H. pylori was capable of binding to human gastric epithelium of nonsecretors. Therefore, we hypothesized that the bacterium might be able to interact with other cell surface receptors to ensure persistent colonization. We here show that the H. pylori adhesin HopQ specifically interacts with human carcinoembryonic antigen-related cell adhesion molecules (CEACAMs). CEACAMs embrace a group of immunoglobulin superfamily-related glycoproteins with a wide tissue distribution. CEACAM1 can be expressed in leukocytes, endothelial and epithelial cells, CEACAM3 and CEACAM8 in granulocytes, CEACAM5 and CEACAM7 in epithelial cells and CEACAM6 in epithelia and granulocytes. In epithelial cells, transmembrane anchored CEACAM1 as well as glycosylphosphatidylinositol-linked CEACAM5, CEACAM6 and CEACAM7 localize to the apical membrane 8. CEACAMs modulate diverse cellular functions such as cell adhesion, differentiation,...

Helicobacter pylori (Hp) strains that carry the cag type IV secretion system (cag-T4SS) to inject the cytotoxin-associated antigen A (CagA) into host cells are associated with peptic ulcer disease and gastric adenocarcinoma. CagA translocation by Hp is mediated by β1 integrin interaction of the cag-T4SS. However, other cellular receptors or bacterial outer membrane adhesins essential for this process are unknown. Here, we identify the HopQ protein as a genuine Hp adhesin, exploiting defined members of the carcinoembryonic antigen-related cell adhesion molecule family (CEACAMs) as host cell receptors. HopQ binds the amino-terminal IgV-like domain of human CEACAM1, CEACAM3, CEACAM5 or CEACAM6 proteins, thereby enabling translocation of the major pathogenicity factor CagA into host cells. The HopQ-CEACAM interaction is characterized by a remarkably high affinity (K from 23 to 268 nM), which is independent of CEACAM glycosylation, identifying CEACAMs as bona fide protein receptors for Hp. Our data suggest that the HopQ-CEACAM interaction contributes to gastric colonization or Hp-induced pathologies, although the precise role and functional consequences of this interaction in vivo remain to be determined.

SUMMARY The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood-group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive but binding is restored by pH neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions; changes during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA’s extraordinary reversible acid-responsiveness enables tight mucosal bacterial adherence while at the same time allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutations and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, and BabA’s adaptive evolution contributes importantly to H. pylori persistence and to overt gastric disease.

The original version of this Article contained incorrect labels in Figs 3b and 4e. In Fig. 3b, the second western blot panel should have been labelled 'CEACAM1'. In Fig. 4e, the final two values on the y axis should have read 'I91A' and 'I91T'. All versions of the Article have been updated. We apologize for any confusion this may have caused.

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